International Journal of Oral Biology

The Korean Academy of Oral Biology (대한구강생물학회)
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Cyclosporin A-induced Gingival Overgrowth is Closely Associated with Regulation Collagen Synthesis by the Beta Subunit of Prolyl 4-hydroxylase and Collagen Degradation by Testican 1-mediated Matrix Metalloproteinase-2 Expression

  • Park, Seong-Hee (Department of Periodontology, Yonsei University College of Dentistry) ;
  • Kim, Jae-Yoen (Department of Oral Biology, Yonsei University College of Dentistry) ;
  • Kim, Hyun-Jeong (Department of Oral Biology, Yonsei University College of Dentistry) ;
  • Park, Kwang-Kyun (Department of Oral Biology, Yonsei University College of Dentistry) ;
  • Cho, Kyoo-Sung (Department of Periodontology, Yonsei University College of Dentistry) ;
  • Choi, Seong-Ho (Department of Periodontology, Yonsei University College of Dentistry) ;
  • Chung, Won-Yoon (Department of Oral Biology, Yonsei University College of Dentistry)
  • Published : 2008.12.31
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Abstract

Gingival overgrowth can cause dental occlusion and seriously interfere with mastication, speech, and dental hygiene. It is observed in 25 to 81% of renal transplant patients treated with cyclosporine A (CsA). CsA-induced gingival overgrowth (CIGO) is caused by quantitative alteration of the extracellular matrix components, particularly collagen. However, the molecular mechanisms involved in the pathogenesis of CIGO remain poorly understood, despite intense clinical and laboratory investigations. The aim of the present work is to identify differentially expressed genes closely associated with CIGO. Human gingival fibroblasts were isolated by primary explant culture of gingival tissues from five healthy subjects (HGFs) and two patients with the CIGO (CIGO-HGFs). The proliferative activity of CsA-treated HGFs and CIGO-HGFs was examined using the MTT assay. The identification of differentially expressed genes in CsA-treated CIGO-HGF was performed by differential display reverse transcriptase-polymerase chain reaction (RT-PCR) followed by DNA sequencing. CsA significantly increased the proliferation of two HGFs and two CIGO-HGFs, whereas three HGFs were not affected. Seven genes, including the beta subunit of prolyl 4-hydroxylase (P4HB) and testican 1, were upregulated by CsA in a highly proliferative CIGO-HGF. The increased P4HB and testican-1 mRNA levels were confirmed in CsA-treated CIGO-HGFs by semiquantitative RT-PCR. Furthermore, CsA increased type I collagen mRNA levels and suppressed MMP-2 mRNA levels, which are regulated by P4HB and testican-1, respectively. These results suggest that CsA may induce gingival overgrowth through the upregulation of P4HB and testican-1, resulting in the accumulation of extracellular matrix components.

Keywords

References

  1. Alliel PM, Perin JP, Jolles P, Bonnet F. Testican, a multidomain testicular proteoglycan resembling modulators of cell social behaviour. Eur J Biochem. 1993:214:347-50 https://doi.org/10.1111/j.1432-1033.1993.tb17930.x
  2. Aoyagi M, Sakaida I, Suzuki C, Segawa M, Fukumoto Y, Okita K. Prolyl 4-hydroxylase inhibitor is more effective for the inhibition of proliferation than for inhibition of collagen synthesis of rat hepatic satellite cells. Hepatol Res. 2002;23:1-6 https://doi.org/10.1016/S1386-6346(01)00162-0
  3. Atilla G, Kutukculer N. Cervicular fluid interleukin-1$\beta$, tumor necrosis factor-$\alpha$, and interleukin-8 levels in renal transplant patients receiving cyclosporin A. J Periodontol. 1998;69:784-90 https://doi.org/10.1902/jop.1998.69.7.784
  4. Barber MT, Savage NW, Seymour GJ. The effect of cyclosporin and lipopolysaccharide on fibroblasts: implications for cyclosporin-induced gingival overgrowth. J Periodontol. 1992;63:397-404 https://doi.org/10.1902/jop.1992.63.5.397
  5. Bartold PM. Regulation of human gingival fibroblast growth and synthetic activity by cyclosporin-A in vitro. J Periodont Res. 1989;24:314-21 https://doi.org/10.1111/j.1600-0765.1989.tb00876.x
  6. Bocock JP, Edgell CS, Marr HS, Erickson AH. Human proteoglycan testican-1 inhibits the lysosomal cysteine protease cathepsin L. Eur J Biochem. 2003;270:4008-15 https://doi.org/10.1046/j.1432-1033.2003.03789.x
  7. Bolzani G, Della Coletta R, Martelli Junior H, Martelli Junior H, Graner E. Cyclosporin A inhibits production and activity of matrix metalloproteinases by gingival fibroblasts. J Periodont Res. 2000;35:51-8 https://doi.org/10.1034/j.1600-0765.2000.035001051.x
  8. Bonnaure-Mallet M, Tricot-Doleux S, Godeau GJ. Changes in extracellular matrix macromolecules in human gingival after treatment with drugs inducing gingival overgrowth. Arch Oral Biol. 1995;40:393-400 https://doi.org/10.1016/0003-9969(94)00187-G
  9. Cai H, Wang CC, Tsou CL. Chaperone-like activity of protein disulfide isomerase in the refolding of a protein with no disulfide bonds. J Biol Chem. 1994;269:24550-2
  10. Cotrim P, de Andrade CR, Martelli-Junior H, Graner E, Sauk JJ, Coletta RD. Expression of matrix metalloproteinases in cyclosporin-treated gingival fibroblasts is regulated by transforming growth factor (TGF)-beta1 autocrine stimulation. J Periodontol. 2002;73:1313-22 https://doi.org/10.1902/jop.2002.73.11.1313
  11. Gagliano N, Moscheni C, Dellavia C, Torri C, Stabellini G, Ferrario VF, Gioia M. Effect of cyclosporin A on human gingival fibroblast collagen turnover in relation to the development of gingival overgrowth: an in vitro study. Biomed Pharmacother. 2004;58:231-8 https://doi.org/10.1016/j.biopha.2003.12.011
  12. Hyland PL, Traynor PS, Myrillas TT, Marley JJ, Linden GJ, Winter P, Leadbetter N, Cawston TE, Irwin CR. The effects of cyclosporin on the collagenolytic activity of gingival fibroblasts, J Periodontol. 2003;74:437-45 https://doi.org/10.1902/jop.2003.74.4.437
  13. John DC, Grant ME, Bulleid NJ. Cell-free synthesis and assembly of prolyl 4-hydroxylase: the role of the betasubunit (PDI) in preventing misfolding and aggregation of the alpha-subunit. EMBO J. 1993;12:1587-95
  14. Kim JY, Park SH, Cho KS, Kim HJ, Lee CK, Park KK, Choi SH, Chung WY. Mechanism of azithromycin treatment on gingival overgrowth. J Dent Res. 2008;87:1075-9 https://doi.org/10.1177/154405910808701110
  15. Ko MK, Kay EP. PDI-mediated ER retention and proteasomal degradation of procollagen I in corneal endothelial cells. Exp Cell Res. 2004;295:25-35 https://doi.org/10.1016/j.yexcr.2003.12.013
  16. Koivu J, Myllyla R. Protein disulfide-isomerase retains procollagen prolyl 4-hydroxylase structure in its native conformation. Biochemistry. 1986;25:5982-6 https://doi.org/10.1021/bi00368a022
  17. Koivu J, Myllyla R. Interchain disulfide bond formation in types I and II procollagen. Evidence for a protein disulfide isomerase catalyzing bond formation. J Biol Chem. 1987;262:6159-64
  18. Koivu J, Myllyla R, Helaakoski T, Pihlajaniemi T, Tasanen K, Kivirikko KI. A single polypeptide acts both as the beta subunit of prolyl 4-hydroxylase and as a protein disulfideisomerase. J Biol Chem. 1987;262:6447-9
  19. Nakada M, Miyamori H, Yamashita J, Sato H. Testican 2 abrogates inhibition of membrane-type matrix metalloproteinases by other testican family proteins. Cancer Res. 2003;63:3364-9
  20. Nakada M, Yamada A, Takino T, Miyamori H, Takahashi T, Yamashita J, Sato H. Suppression of membrane type I matrix metalloproteinase (MMP)-mediated MMP-2 activation and tumor invasion by testican 3 and its splicing variant gene product, N-Tes. Cancer Res. 2001;61:8896-902
  21. Nares S, Na MG, Dill RE, Cutler CW, Lacopino AM. Cyclosporin A upregulates platelet-derived growth factor B chain in human hyperplastic gingiva. J Periodontol. 1996;67:271-8 https://doi.org/10.1902/jop.1996.67.3.271
  22. Park JI, Lee GS, Jeong YJ, Kim BK, Kim JH, Lim HS, Kim SH, Kim WJ, Jung JY. Involvement of antiapoptotic signals in rat PC12 cells proliferation by cyclosporin A treatment. Int J Oral Biol. 2007;32:51-7
  23. Schincaglia GP, Forniti F, Cavallini R, Piva R, Calura G, Del Senno L. Cyclosporin-A increases type I procollagen production and mRNA level in human gingival fibroblasts in vitro. J Oral Pathol Med. 1992;21:181-5 https://doi.org/10.1111/j.1600-0714.1992.tb00098.x
  24. Swarga JD, Mohamed HP, Irwin O. Upregulation of keratinocyte growth factor in cyclosporin A-induced gingival overgrowth. J Periodontol. 2001;72:745-52 https://doi.org/10.1902/jop.2001.72.6.745
  25. Tipton DA, Stricklin GP, Dabbous MK. Fibroblast heterogeneity in collagenolytic response to cyclosporine. J Cell Biochem. 1991;46:152-65 https://doi.org/10.1002/jcb.240460209
  26. Tyldesley WR, Rotter E. Gingival hyperplasia induced by cyclosporin A. Brit Dent J. 1984;157:305-9 https://doi.org/10.1038/sj.bdj.4805474
  27. Wysocki GP, Gretzinger HA, Laupacis A, Ulan RA, Stiller CR. Fibrous hyperplasia of the gingiva: A side effect of cyclosporin A therapy. Oral Surg Oral Med Oral Pathol. 1983;55:274-8 https://doi.org/10.1016/0030-4220(83)90327-4
  28. Yamada H, Nishimura F, Naruishi K, Chou HH, Takashiba S, Albright GM, Nares S, Lacopino AM, Murayama Y. Phenytoin and cyclosporin A suppress the expression of MMP-1, TIMP-1, and cathepsin L, but not cathepsin B in cultured gingival fibroblasts. J Periodontol. 2000;71:955-60 https://doi.org/10.1902/jop.2000.71.6.955